{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:26:17Z","timestamp":1791977177393,"version":"4.4.0"},"reference-count":55,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Chemours Company FC, LLC"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:p>GenX is an alternative to environmentally persistent long-chain perfluoroalkyl and polyfluoroalkyl substances. Mice exposed to GenX exhibit liver hypertrophy, elevated peroxisomal enzyme activity, and other apical endpoints consistent with peroxisome proliferators. To investigate the potential role of peroxisome proliferator-activated receptor alpha (PPAR\u03b1) activation in mice, and other molecular signals potentially related to observed liver changes, RNA sequencing was conducted on paraffin-embedded liver sections from a 90-day subchronic toxicity study of GenX conducted in mice. Differentially expressed genes were identified for each treatment group, and gene set enrichment analysis was conducted using gene sets that represent biological processes and known canonical pathways. Peroxisome signaling and fatty acid metabolism were among the most significantly enriched gene sets in both sexes at 0.5 and 5 mg\/kg GenX; no pathways were enriched at 0.1 mg\/kg. Gene sets specific to the PPAR\u03b1 subtype were significantly enriched. These findings were phenotypically anchored to histopathological changes in the same tissue blocks: hypertrophy, mitoses, and apoptosis. In vitro PPAR\u03b1 transactivation assays indicated that GenX activates mouse PPAR\u03b1. These results indicate that the liver changes observed in GenX-treated mice occur via a mode of action (MOA) involving PPAR\u03b1, an important finding for human health risk assessment as this MOA has limited relevance to humans.<\/jats:p>","DOI":"10.1177\/0192623320905803","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T04:52:55Z","timestamp":1583470375000},"page":"494-508","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":74,"title":["Assessment of the Mode of Action Underlying the Effects of GenX in Mouse Liver and Implications for Assessing Human Health Risks"],"prefix":"10.1177","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7543-8336","authenticated-orcid":false,"given":"Grace A.","family":"Chappell","sequence":"first","affiliation":[{"name":"ToxStrategies, Inc, Asheville, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad M.","family":"Thompson","sequence":"additional","affiliation":[{"name":"ToxStrategies, Inc, Katy, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Experimental Pathology Laboratories, Sterling, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Cullen","sequence":"additional","affiliation":[{"name":"North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Klaunig","sequence":"additional","affiliation":[{"name":"Indiana University, School of Public Health, Bloomington, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie C.","family":"Haws","sequence":"additional","affiliation":[{"name":"ToxStrategies, Inc, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,3,6]]},"reference":[{"key":"bibr1-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm128"},{"key":"bibr2-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1002\/ieam.258"},{"key":"bibr3-0192623320905803","unstructured":"Agency for Toxic Substances and Disease Registry. Toxicological Profile for Perfluoroalkyls (Draft for Public Comment). Atlanta, GA: US Department of Health and Human Services, Public Health Service; 2018."},{"key":"bibr4-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.10009"},{"key":"bibr5-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2015.12.006"},{"key":"bibr6-0192623320905803","first-page":"1","author":"Thompson CM","year":"2019","journal-title":"J Appl Toxicol"},{"key":"bibr7-0192623320905803","unstructured":"US Environmental Protection Agency. Human Health Toxicity Values for Hexafluoropropylene Oxide (HFPO) Dimer Acid and Its Ammonium Salt (CASRN 13252-13-6 and CASRN 62037-80-3) Also Known as \u201cGenX Chemicals\u201d. (Public Comment Draft). 2018. https:\/\/www.epa.gov\/sites\/production\/files\/2018-11\/documents\/genx_public_comment_draft_toxicity_assessment_nov2018-508.pdf. Accessed November 14, 2018."},{"key":"bibr8-0192623320905803","unstructured":"MacKenzie SA. H-28548: Subchronic Toxicity 90-day Gavage Study in Mice E.I. du Pont de Nemours and Company DuPont Haskell Global Centers for Health & Environmental Sciences. 2010. https:\/\/hero.epa.gov\/hero\/index.cfm\/reference\/details\/reference_id\/4229663. Accessed January 30, 2018."},{"key":"bibr9-0192623320905803","unstructured":"Edwards TL. An Oral (Gavage) Reproduction\/Developmental Toxicity Screening Study of H-28548 in Mice (DuPont). Ashland, Ohio: WIL Research Laboratories, LLC; 2010. https:\/\/hero.epa.gov\/hero\/index.cfm\/reference\/details\/reference_id\/4222148. 2010. Accessed January 30, 2018."},{"key":"bibr10-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1177\/0192623315625859"},{"key":"bibr11-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3376"},{"key":"bibr12-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2011.10.014"},{"key":"bibr13-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2017.07.031"},{"issue":"1","key":"bibr14-0192623320905803","first-page":"85","volume":"157","author":"Dean JL","year":"2017","journal-title":"Toxicol Sci"},{"key":"bibr15-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1021\/es505199f"},{"key":"bibr16-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-017-1536-9"},{"key":"bibr17-0192623320905803","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2018.00484"},{"key":"bibr18-0192623320905803","volume-title":"Guice for the Care and Use of Laboratory Animals","author":"National Research Council","year":"2011","edition":"8"},{"key":"bibr19-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1177\/0192623310386499"},{"issue":"8","key":"bibr20-0192623320905803","first-page":"1605","volume":"57","author":"Krajewska M","year":"1997","journal-title":"Cancer Res"},{"key":"bibr21-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178302"},{"key":"bibr22-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"bibr23-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1289\/EHP1937"},{"key":"bibr24-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx153"},{"key":"bibr25-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1089\/152791601750294344"},{"key":"bibr26-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.1.29"},{"key":"bibr27-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn653"},{"key":"bibr28-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1018"},{"key":"bibr29-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"bibr30-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt111"},{"key":"bibr31-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"bibr32-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty878"},{"key":"bibr33-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"},{"key":"bibr34-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1177\/002215540205000401"},{"key":"bibr35-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M005363"},{"key":"bibr36-0192623320905803","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00445"},{"key":"bibr37-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1024"},{"key":"bibr38-0192623320905803","doi-asserted-by":"publisher","DOI":"10.3109\/10408444.2013.835784"},{"key":"bibr39-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1080\/713608372"},{"key":"bibr40-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1177\/0192623312448935"},{"key":"bibr41-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1289\/EHP4372"},{"key":"bibr42-0192623320905803","unstructured":"National Toxicology Program. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Perfluorooctanoic Acid (CAS No. 335-67-1) Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley\u00ae SD\u00ae) Rats; Technical Report 598 (Peer Review Draft). The National Toxicology Program; 2019."},{"key":"bibr43-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs318"},{"key":"bibr44-0192623320905803","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.5307"},{"key":"bibr45-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/j.comtox.2018.12.007"},{"key":"bibr46-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2017.05.013"},{"key":"bibr47-0192623320905803","first-page":"2010","author":"Rosen MB","year":"2010","journal-title":"PPAR Res"},{"key":"bibr48-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1621\/nrs.13002"},{"key":"bibr49-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.247296"},{"key":"bibr50-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2017.11.003"},{"key":"bibr51-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-017-2094-7"},{"key":"bibr52-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/132960"},{"key":"bibr53-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgi329"},{"key":"bibr54-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(95)03513-3"},{"key":"bibr55-0192623320905803","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.11.2029"}],"container-title":["Toxicologic Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0192623320905803","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0192623320905803","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0192623320905803","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:40:57Z","timestamp":1777653657000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0192623320905803"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,6]]},"references-count":55,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1177\/0192623320905803"],"URL":"https:\/\/doi.org\/10.1177\/0192623320905803","relation":{},"ISSN":["0192-6233","1533-1601"],"issn-type":[{"value":"0192-6233","type":"print"},{"value":"1533-1601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,6]]}}}